Summary Glial activation and production of proinflammatory mediators contribute to the pathogenesis of neuropathic pain. Pre-clinical studies implicate microglia, the macrophages of the central nervous system (CNS), as critical early regulators in the development of peripheral nerve injury-induced neuropathic pain. However, other studies indicate that microglial activation and the production of various proinflammatory factors play a beneficial role in nerve regeneration and functional recovery following nerve injury. Moreover, our preliminary studies show that similar to peripheral macrophages, spinal cord microglia exhibit a proinflammatory phenotype at early time points and an anti-inflammatory phenotype at later time points following spinal nerve L5 transection (L5Tx, a well-established murine model of neuropathic pain). We propose that these two microglial activation states correspond to unique sets of microglial functions. By optimally regulating microglial activation rather than completely inhibiting the activation of microglia, we can potentially limit the contribution of microglia to the development of neuropathic pain while simultaneously preserving the beneficial properties of microglia in nerve regeneration. We believe that CD137 ligand (CD137L) expressed on microglial surface acts in a proinflammatory manner and that negatively modulating CD137L can potentially shift the pro- vs. anti-inflammatory balance in activated microglia towards an anti- inflammatory state. However, most of the known functions of CD137L have been obtained from studies on peripheral immune cells. The role of CD137L in CNS microglia has not been studied extensively and the role of microglial CD137L in the development of neuropathic pain is unknown. In this study, we will determine the role of microglial CD137L in the pathophysiology of peripheral nerve injury-induced neuropathic pain through the examination of two murine models of neuropathic pain. We hypothesize that microglial CD137L is involved in the development of peripheral nerve injury -induced pain-like behaviors and that negatively modulating CD137L can promote a shift in microglial activation towards an anti- inflammatory state and thus reduce peripheral nerve injury-induced pain-like behaviors. This central hypothesis will be tested via three specific aims: 1) Characterize the involvement of CD137L in peripheral nerve injury-induced pain-like behaviors. Pain-like behaviors will be tested in mice with and without CD137L expression. 2) Evaluate the activation status of spinal cord microglia following peripheral nerve injury in relation to the expression of microglial CD137L. Microglial activation will be monitored through assessing microglial phenotype via flow cytometry. And 3) determine the involvement of CD137-dependent vs. CD137- independent pathways in peripheral nerve injury-induced, CD137L-mediated pain-like behaviors and microglial responses. In sum, we believe that the investigation of CD137L could lead to novel treatment that could significantly reduce neuropathic pain while has minimal adverse impact on nerve recovery.